Impact of secondary mitral regurgitation on survival in atrial and ventricular dysfunction

Background Natural history of atrial and ventricular secondary mitral regurgitation (SMR) is poorly understood. We compared the impact of the degree of SMR on survival between atrial and ventricular dysfunction. Methods We conducted a retrospective cohort study of patients who underwent echocardiography in a healthcare network between 2013–2018. We compared the survival of patients with atrial and ventricular dysfunction, using propensity scores developed from differences in patient demographics and comorbidities within SMR severity strata (none, mild, moderate or severe). We fitted Cox proportional hazards models to estimate the risk-adjusted hazards of death across different severities of SMR between patients with atrial and ventricular dysfunction. Results Of 11,987 patients included (median age 69 years [IQR 58–80]; 46% women), 6,254 (52%) had isolated atrial dysfunction, and 5,733 (48%) had ventricular dysfunction. 3,522 patients were matched from each arm using coarsened exact matching. Hazard of death in atrial dysfunction without SMR was comparable to ventricular dysfunction without SMR (HR 1.1, 95% CI 0.9–1.3). Using ventricular dysfunction without SMR as reference, hazards of death remained higher in ventricular dysfunction than in atrial dysfunction across increasing severities of SMR: mild SMR (HR 2.1, 95% CI 1.8–2.4 in ventricular dysfunction versus HR 1.7, 95%CI 1.5–2.0 in atrial dysfunction) and moderate/severe SMR (HR 2.8, 95%CI 2.4–3.4 versus HR 2.4, 95%CI 2.0–2.9). Conclusions SMR across all severities were associated with better survival in atrial dysfunction than in ventricular dysfunction, though the magnitude of the diminishing survival were similar between atrial and ventricular dysfunction in increasing severity of SMRs.

SMR across all severities were associated with better survival in atrial dysfunction than in ventricular dysfunction, though the magnitude of the diminishing survival were similar between atrial and ventricular dysfunction in increasing severity of SMRs.

Background
Atrial functional mitral regurgitation (AFMR) is a form of secondary mitral regurgitation (SMR) increasingly gaining recognition [1]. AFMR is thought to occur secondary to dilated and dysfunctional atrium in the absence of ventricular dysfunction [2]. This contrasts the SMR of ventricular etiology commonly seen in ischemic cardiomyopathy and dilated cardiomyopathy. While the different etiologies and potentially effective treatments are recognized between the two subtypes of SMR [3,4], the natural history of patients with different severities of SMR related to atrial dysfunction has not been well described beyond small single-center series [5,6]. Understanding the difference in survival between comparable severities of SMR in atrial versus ventricular dysfunction may further inform the timing of surveillance and potential therapeutic options [4].
Although the etiology of SMR in patients with isolated atrial dysfunction differs from SMR resulting from ventricular dysfunction, current guidelines do not clearly distinguish management [7]. In AFMR, insufficient leaflet remodeling in response to the annular dilatation appears to be the driver of the disease [3] and SMR may temporarily improve after correction of atrial fibrillation [8,9]. Therefore, the optimal surgical approach and threshold for intervention in AFMR may differ from ventricular SMR [10][11][12]. Understanding the potential difference in the impact of SMR on survival in patients with atrial dysfunction relative to ventricular dysfunction may help guide the threshold for intervention.
Leveraging a large echocardiogram database of a health care system, we aimed to compare the impact of different severities of SMR on survival between those with atrial and ventricular dysfunctions.

Data source and patient population
This retrospective cohort study was conducted at Yale-New Haven Health, a large healthcare network in the United States, encompassing 5 acute care hospitals in academic and community settings and over 120 outpatient clinics at satellite locations throughout Connecticut [13]. The system-wide electronic medical record database was queried to identify patients age � 18 years who received complete (as opposed to focused exam) transthoracic echocardiogram for any indication between July 1, 2013, and October 31, 2018, either during inpatient or outpatient encounters. These included echocardiograms obtained from 32 sites.
Structured data fields on echocardiographic parameters and full text of the cardiology attendings' echocardiogram reads were extracted. We identified patients with isolated atrial dysfunction or ventricular dysfunction using the following definitions: isolated atrial dysfunction was defined as enlarged left atrium (LA dimension index >34 mm/m 2 ) [14] with LVEF�55% or history of atrial fibrillation or flutter with LVEF �55% based on prior studies [15]. Ventricular dysfunction was defined as those with LVEF <55% regardless of atrial dimension or atrial arrhythmia histories. We adopted this definition while recognizing that prior studies have variably defined atrial dysfunction [16]. LVEF was estimated using 2D or 3D volumetric tracing. We refer to SMR as MR of non-primary etiology encompassing ventricular or atrial dysfunction.
We restricted the cohort to those without significant concomitant valvular pathologies and MR of primary etiologies by the following exclusion criteria: those with primary MR of any severity (rheumatic, prolapsed, degenerative, or myxomatous findings), mitral stenosis of any severity, greater-than-mild aortic stenosis or aortic regurgitation, those with findings of vegetation or intracardiac mass or thrombus. Patients with prosthetic valves were also excluded (Fig 1). Additionally, patients with missing ejection fraction or left atrial dimension index were excluded. In patients with multiple echocardiograms, the study with the earliest date was analyzed. These criteria yielded 11,987 echocardiograms obtained on unique patients with either atrial or ventricular dysfunction, with secondary MR grades ranging from none to severe.
The Institutional Review Board at Yale University approved this study, and individual consent was waived for the minimal risk nature of the study.

Outcome
The outcome of the study was cumulative survival since the time of echocardiogram. Patient data were linked to the Connecticut Vital Statistics data curated by the Connecticut State Department of Public Health to ascertain the date of death. The state's vital statistics record captures deaths of all Connecticut residents, whether the death occurred in or out of the state. The last date of follow-up available via the vital statistics data was October 15, 2019.

Echocardiographic and patient characteristics, missing values
Demographic variables extracted from the medical records system were age at the time of echocardiogram, sex, and race. Comorbidities were selected based on prior studies and identified via the patient's past medical history that were grouped based on the corresponding International Classification of Diseases 10 th revision, Clinical Modification (ICD-10-CM) codes [17]. The extracted comorbidities were updated and verified by the care provider at each clinical encounter and were distinct from those used for billing purposes. The comorbidities were: heart failure, diabetes, hypertension, myocardial infarction, peripheral vascular disease, prior coronary artery bypass graft surgery, cerebrovascular disease, chronic pulmonary obstructive disease, liver disease, renal failure, iron-deficiency anemia, rheumatoid disease, peptic ulcer disease, dementia, depression, cancer, substance use, and acquired immunodeficiency syndrome (S1 Table) [17]. In addition to the severity of the valvular disease, the left ventricular ejection fraction and left atrial volume index was extracted from the echocardiogram report. This was missing in 1,234 patients, who were excluded. Patient age, sex, and race had no missing values. Comorbidity variables defined via ICD-10 codes did not have any missing values as the absence of ICD-10 codes corresponding to the condition of interest was defined as the absence of a condition consistent with methodologies adopted by existing studies.

Interval mitral valve surgery, transcatheter mitral valve interventions, and ablations
We linked the echocardiogram database with the institutional Society of Thoracic Surgeons Adult Cardiac Surgery Database and the list of cardiovascular procedures that the patient underwent within our health system since the time of the index echocardiogram and October 15, 2019. Mitral valve surgery (mitral valve replacement or repair) or mitral valve intervention (transcatheter edge-to-edge repair or transcatheter mitral valve replacement) was treated as the time-varying covariate in the Cox proportional hazard models. Similarly, catheter-based ablations performed for atrial fibrillation or flutter were identified and matched.

Statistical analysis
Continuous variables were reported as medians and interquartile ranges (IQR). Categorical variables were expressed as frequencies and percentages. Differences in demographic variables between patients with atrial and dysfunction were compared using Wilcoxon rank-sum tests for non-normally distributed continuous variables and the chi-squared tests for categorical variables.
Kaplan-Meier plots and corresponding log-rank tests were calculated to evaluate unadjusted and matched survival estimates. The study aimed to compare the potential impact of the degree of SMR on survival between patients with isolated atrial dysfunction and patients with ventricular dysfunction. To account for potential confounding between survival and atrial or ventricular dysfunction, matching between isolated atrial and ventricular dysfunction groups was performed by first estimating propensity scores from a multivariable logistic regression model using the covariates listed below. The groups were then matched with a 1:1 coarsened exact nearest-neighbor matching method without replacement using the propensity score and matching the groups exactly on the severity of SMRs [18]. Observations without nearest neighbor match were discarded. This method was used to balance the observed patient characteristics between the two groups across different severity strata of SMRs. The quality of matching was evaluated using the Love plot depicting the standard mean difference of the groups in each covariate and the density plot of the propensity score. We defined the standard mean difference <0.1 as the threshold for balanced matching [19]. We fitted a bivariate Cox proportional hazard model on the matched dataset, including both ventricular and atrial dysfunction patients, to assess the hazard of time-to-death associated with the severity of SMR occurring with atrial or ventricular dysfunction. Hazard ratios for each combination of ventricular versus atrial dysfunction and SMR severities were calculated using the group with ventricular dysfunction without SMR as the reference group.
The propensity score was calculated from the following covariates: atrial or ventricular dysfunction, age, sex, race, inpatient status (in vs. outpatient), heart failure, diabetes, hypertension, myocardial infarction, peripheral vascular disease, prior coronary artery bypass graft surgery, cerebrovascular disease, chronic pulmonary obstructive disease, liver disease, renal failure, iron-deficiency anemia, rheumatoid disease, peptic ulcer disease, dementia, depression, cancer, substance use, and acquired immunodeficiency syndrome. Additionally, mitral valve surgery or intervention and ablation for atrial arrhythmias were matched on time from echo to intervention.
As a sensitivity analysis to assess the differential impact of SMR on the hazard of death between patients with atrial and ventricular dysfunction, Cox models were fitted separately for atrial and ventricular dysfunction groups using the demographic, comorbidity, and SMR severity as time-independent covariates and mitral valve surgery or intervention as a timedependent covariate. The proportional hazard assumption was evaluated for the MR severity and atrial or ventricular dysfunction using the survival plot, which satisfied the assumption. Because the coefficients of different models cannot be directly compared for the potentially varying residuals [20], we estimated the number of deaths during the constant follow-up duration under the simulated condition of every patient having no SMR, mild SMR, and moderate or severe SMR. This was done separately for patients with atrial dysfunction and ventricular dysfunction. By comparing the percent changes in the number of deaths under all patients having no SMR to all patients having severe SMR, we estimated the impact of increasing severity of SMR on the hazard of death. We characterized the differential impact of SMR between patients with atrial and ventricular dysfunction by comparing the estimated percent increase in the number of deaths as the severity of SMR increased.

Results
Among the 11,987 patients, there were 6,254 (52.2%) patients with isolated atrial dysfunction and 5,733 (47.8%) patients with ventricular dysfunction. The median age of the cohort was 69 (IQR 58, 80) years with 46% being male and 80% of echocardiogram performed in an inpatient setting. Patients with atrial dysfunction were older and more frequently female. Compared with patients with ventricular dysfunction, some atherosclerotic comorbidities were less common in patients with atrial dysfunction, such as the history of diabetes, peripheral vascular disease, prior CABG, and myocardial infarction. Liver disease, cancer, and substance use were more common in patients with atrial dysfunction. Moderate or severe MR was more frequently present in patients with ventricular dysfunction (757 [12%] versus 1,366 [24%], p<0.001) ( Table 1).
In atrial dysfunction, mild or greater SMR occurred more commonly in women while it occurred more commonly in men in ventricular dysfunction (Table 2 for atrial dysfunction, Table 3 for ventricular dysfunction). Unadjusted survival was lower in patients with a higher grade of SMR in both ventricular and atrial dysfunctions (Fig 2). Matching yielded 7,044 patients (3,522 in each group). Patient characteristics were balanced except for the variables not used to generate propensity scores, which were ejection fraction and left ventricular dimensions ( Table 4). The distribution of the propensity score before and after matching (S1 Fig) and the standardized mean difference for each covariate (S2 Fig) indicated that the groups were matched well.
Survival curves of the matched group demonstrated comparable survival between atrial and ventricular dysfunction with no or trace SMR. In contrast, the survival was worse in ventricular dysfunction than in atrial dysfunction in patients with mild, moderate, or severe SMR (Fig  3). Cox proportional hazard model fitted on the matched group also demonstrated that the hazard of death was not significantly different between atrial and ventricular dysfunctions in patients with no or trace SMR while the hazard was higher in patients with ventricular dysfunction in mild, moderate, and severe SMR than in patients with atrial dysfunction (Fig 4).
The sensitivity analysis using the Cox proportional hazards model also demonstrated an increasing number of expected deaths with increasing severity of SMR in both atrial and ventricular dysfunctions. The magnitude of increase with a more severe SMR was larger in ventricular dysfunction than in atrial dysfunction (S2 Table).

Discussion
Understanding the difference in the prognosis of SMR between those related to atrial versus ventricular dysfunction is important considering the variable treatment response to interventions in patients with functional MR [5,21,22]. In a cohort of patients with echocardiograms performed in academic and community settings, we demonstrated that across comparable severities of MR, patients with both atrial and ventricular dysfunction portended worse survival with higher degrees of SMR. Additionally, atrial dysfunction had better survival than patients with ventricular dysfunction within comparable strata of SMR severity. These findings suggest that more severe SMR could carry a higher burden in ventricular dysfunction relative to atrial dysfunction. Different prognosis in the two different types of SMR warrants further investigation to determine the optimal threshold for intervention in each type of SMR.
This study adds to the current literature in several ways. First, the prognostic significance of SMR related to atrial and ventricular dysfunctions has been suspected [23] but direct comparisons have been limited only to small studies with an inconclusive characterization of survivals Continuous variables are expressed in terms of median (interquartile range) and categorical variables are expressed as N (%). CABG = coronary artery bypass graft; AIDS = acquired immunodeficiency syndrome. LVIDd = left ventricular internal diameter (end-diastolic); LVIDs = left ventricular internal diameter (end-systolic).
https://doi.org/10.1371/journal.pone.0277385.t003 [24]. Clinical characteristics and optimal treatment approaches for MR related to ventricular dysfunction are well characterized by studies focusing on SMR occurring in the setting of ischemic cardiomyopathy [12,25]. However, the outcomes of SMR related to atrial dysfunction remained elusive, especially in direct comparisons to those in SMR associated with ventricular dysfunction. Perhaps consequently, the current guidelines do not distinguish the treatment approach between the two types of SMR [26]. The current surveillance recommendation may be inadequate for milder forms of SMR and does not distinguish atrial from ventricular SMR [27]. A single-center study reported superior survival in AFMR compared with ventricular MR in patients who underwent mitral valve operation [5], but how such findings may translate into the broader cohort of patients with MR before the selection for surgical intervention had been unclear. Our study of patients who underwent echocardiograms in the community and academic sites demonstrated that SMR related to atrial and ventricular dysfunctions differ in patient characteristics and survival. However, both forms of SMR were associated with an increased risk of death compared to patients without SMR, supporting the notion that both forms of severe SMR require close monitoring and treatment. The observed higher hazards of death associated with mild SMR, which has been thought of as a relatively benign entity, is corroborated by prior studies demonstrating increased morality risk associated with mild SMR [27,28].
The optimal treatment approach in terms of mitral valve intervention likely relates to the mechanistic working of MR and their prognostic significance. The simple annular dilatation alone may not explain the majority of MR occurring in the setting of atrial dysfunction. Instead, some studies have suspected it is the discrepant loading condition between LA and LV that results in malcoaptation. In such settings, a simple annuloplasty alone may not be beneficial, and in fact, the optimal treatment may be medical therapy such as hypertension treatment to optimize afterload. However, prior studies on the medical management of HFpEF  have not identified beneficial therapies in this heterogeneous population [29]. Prognostically, as we demonstrated, AFMR may be less harmful towards survival compared with MR occurring in ventricular dysfunction. Therefore, understanding the optimal treatment threshold and approach further requires mechanistic insights into the etiology of the AFMR. Proposed treatment for AFMR is evolving with increasing mechanistic understanding of how atrial dysfunction may lead to MR [3]. A single-center observational study suggested that AFMR may be better treated with mitral annuloplasty than with replacement, owing to the isolated nature of annular dilatation in the absence of ventricular remodeling [30]. Routine catheter-based ablation or Cox-MAZE operation to treat atrial arrhythmias at the time of mitral valve operation is likely important. The role of transcatheter edge-to-edge repair for AFMR remains elusive as randomized trials on the application of MitraClip (Abbott Vascular, Menlo Park, CA) for functional MR excluded patients with AFMR [21,22]. Identifying the optimal treatment approach for AFMR remains a topic for future investigation.

Limitations
The small sample size of the patients with severe SMR precluded further stratification between moderate and severe MR. We demonstrated the incrementally worse survival across increasing SMR severities, and the finding likely extrapolates to the difference in moderate and severe MR with a larger sample. However, beyond prognostic significance, we could not infer differential therapeutic approach for different types of SMR. The population included those who underwent echocardiograms related to a health-system encounter and may not generalize to the general population in the community. Nevertheless, our inclusion of academic and community sites within the health-system network enabled us to capture individuals with a broad range of characteristics and likely minimized center-specific patient selection. Measurements important to further characterizing the ventricular function, such as left-ventricular end-diastolic dimension, were not consistently available and were not used in adjustment or matching in the main analysis but were descriptively reported. Inter-rater variability may exist among cardiologists who interpreted the echocardiograms. Although likely small in number, patients who relocated to outside of Connecticut and died would not have been captured by the vital statistics used in this study. We were not able to delineate the etiology of atrial dilation. This is an important limitation, as physiologic and pathologic enlargement of the left atrium may have prognostic differences [31].

Conclusions
In this study of echocardiograms obtained across a large health system encompassing academic and community settings, patients with isolated atrial dysfunction had better survival compared with ventricular dysfunction across comparable severities of secondary mitral regurgitation. Substantially worse survival associated with mild or greater SMR in both atrial and ventricular dysfunctions warrant close monitoring at the onset of SMR irrespective of the type. Prospective evaluation of such close monitoring is needed to confirm the finding of the study.
Supporting information S1 Table.